The function of the cytoplasmic tail of the IgE antigen-receptor during the IgE response in vivo

The number of allergic diseases increases annually. Yet, the investigation of the molecular cause of the disease up to now was not possible with classical medical techniques. The modern molecular biology allows us to answer questions concerning these topics. Normally, our immune system is able to estimate the source of danger and distinguish between harmless and pathogenic substances. But sometimes the estimation fails and a harmless substance is recognised as a dangerous one. In this case, the substance acts as antigen and activates the immune system. Exactly this happens when a person takes contact with a harmless substance, i.E plant pollen. The classical allergic reaction starts seconds or minutes after antigen contact and is committed by antibodies, produced by a special class of lymphocytes. These antibodies belong to the IgE subclass and are responsible for the hyper reactivity reaction. In healthy individuals, IgE plays only a minor role. However, in allergic people the situation is completely different and IgE antibodies trigger the allergic response. The mechanisms behind are not completely understood which results in therapeutic possibilities restricted to symptom control. To develop basic therapies a lot of questions concerning the regulation of IgE expression have to be investigated. IgE itself can be secreted into the blood or expressed as membrane receptor on the surface of specific B- lymphocytes. In the membrane form, IgE is responsible for the induction of immunological memory and differentiation of IgE producing plasma cells. In the secreted form, the antibodies fulfil all tasks of the immune response: they trace the antigen and contribute to its destruction. The regulation of the production of IgE is very complex. A lot of regulators, positively and negatively, influence the synthesis of IgE. Experiments in our laboratory could show that not only regulatory molecules but also the membrane IgE itself controls the quantity and quality of the IgE produced. Thus, the IgE antigen receptor itself regulates a signal transduction that finally expresses a high level of IgE which is responsible for the induction of allergic diseases. The knowledge about the function of these regulators is the prerequisite for the development of useful therapies of allergic diseases. However, the cloning of these regulatory proteins is very difficult. Therefore we use and used the murine system as model system for the cloning experiment. The advantage of the mouse system is the fact that all genes that are part of the regulatory cascade of the IgE expression can easily be mutated or deleted. The loss of function phenotype of these mouse strains allows conclusions on the function of the mutated/deleted protein. We were able to construct mouse lines which clearly indicated the direct function of the antigenreceptor during the immune response. The experiments also indicated that the cytoplasmic tail is necessary for the selection of high affinity antibodies but has no function on the regulation of the mutational process. Additionally, we could show that the IgE-response is short- lived which means that in the future IgE-memory has to be newly defined. This aspect becomes more and more interesting, because the knowledge of these processes leads to new therapeutic possibilities and indicates that the cytoplasmic tail is a suitable target for allergy treatment.